Anticonvulsant and central nervous system-depressing bis (fluorophenyl) alkylamides and their uses

ABSTRACT

Bis(Fluorophenyl)alkylamides have been chemically synthesized which possess beneficial pharmacological properties (e.g., anticonvulsant activity) useful for the treatment of neurological diseases or disorders, such as, for example, epilepsy, convulsions, and seizure disorders. The preferred compounds of the invention also cause little sedation and have high therapeutic and protective indices in animal models of epilepsy. These compounds further possess long pharmacologic half-lives, which, in practical clinical therapeutic application, should translate into once-a-day dosing, of great benefit to patients suffering from these diseases and/or disorders. These compounds may also be of further clinical utility in the treatment of other diseases and disorders of the central and peripheral nervous systems, or diseases or disorders affected by them, including, but not limited to, spasticity, skeletal muscle spasms and pain, restless leg syndrome, anxiety and stress, and bipolar disorder.

RELATED APPLICATIONS

[0001] This application is a Continuation of International ApplicationNo. PCT/US98/26315, filed Dec. 9, 1998 which claims the benefit ofProvisional Application No. 60/069,005, filed Dec. 10, 1997.

FIELD OF THE INVENTION

[0002] The present invention relates to compounds useful in treatingpathological conditions, such as convulsions and spasticity, withoutproducing undesirable excessive sedation or muscle weakness in animalsubjects, including humans. More particularly, the invention relates tothe preparation, biological activities, and therapeutic uses of3,3-bis(3-fluorophenyl)propionamide and related compounds in patientssuffering from pathologies of this nature.

BACKGROUND OF THE INVENTION

[0003] The following is a description of relevant art, none of which isadmitted to be prior art to the claims.

[0004] A number of pathological states, diseases, and disorders arecharacterized by a profound aberration in the normal function of thecentral nervous system (CNS). Such conditions include multiplesclerosis, strokes, spinal cord injuries, chronic neurodegenerativedisorders and diseases such as Parkinson's and Huntington's diseases,Alzheimers disease, amyotrophic lateral sclerosis (ALS; Lou Gehrigdisease), and epilepsy. At the clinical level, these states usually onlyrespond to pharmacologic intervention with compounds or substances thatpossess significant activity at the level of the CNS.

[0005] Because of the availability of reasonably predictive andexperimentally accessible animal models of convulsant states, a numberof clinically useful anticonvulsants have been prepared and developed inthe 20th century, many from compounds originally developed assedative-hypnotic or anxiolytic agents. In current medical practice,many of the compounds in clinical use for the symptomatic treatment ofspasticity are various kinds of central muscle relaxants, usually havingbeen first developed for the treatment of other clinical indications.Most of these medicinal agents are fraught with undesirable,troublesome, and poorly tolerated side effects in the treatment ofspastically, and all are far from being ideal clinical entities in thisapplication (MERCK INDEX, 12^(th) ed., Merck & Co., Rahway, N.J., 1996).

[0006] Similarly, many anticonvulsants and antispastics in clinical useare plagued by the occurrence of significant side effects which limittheir long-term clinical utility, including troublesome daytime sedation(drowsiness, cognitive blunting, and/or “hangover”), muscular weakness,tolerance, gingivitis and gum recession (gingival hyperplasia), andpotentially fatal blood dyscrasias and hepatotoxicities (some of whichare or can be fatal) Among these agents are the benzodiazepines, whichcan cause cognitive blunting. Other agents, such as valproate andphenytoin (Dilantin) can cause or produce hepatotoxicity and gingivalhyperplasia, respectively, among other side effects limiting theirtherapeutic potential. Many of these side effects are especiallytroubling in the clinical treatment of pediatric epilepsy (or epilepsyin children). Thus, there is a clear and persistent need for thedevelopment of new clinical entities with improved side effect profilesand efficacy for the treatment of convulsive states or conditions.

[0007] In addition, there is a need for the development of new clinicalentities with improved side effect profiles and efficacy for thetreatment of spasticity and epilepsy. Certain bis(fluorophenyl)alkylamides, are described in U.S. Ser. No. 08/873,011, filed Jun. 11,1997, which is commonly owned with the present invention, and is herebyincorporated herein by reference in its entirety.

SUMMARY OF THE INVENTION

[0008] Accordingly, it is an object of the present invention to providecompounds and a novel therapeutic approach for the treatment of variouspathologies by effecting a modulation in CNS activity without producingexcessive sedation, muscle weakness, fatigue, gingival hyperplasia,blood dyscrasias, or hepatotoxicity.

[0009] It also is an object of the present invention to provide a methodfor alleviating one or more symptoms associated with a condition, suchas convulsions and spasticity, that is ameliorated by means ofmodulating CNS activity.

[0010] It is another object of the present invention to provide a novelanticonvulsant therapy.

[0011] In accomplishing these and other objectives, there has beenprovided, according to one aspect of the present invention, a use of anovel compound selected from the group consisting of3,3-bis(3-fluorophenyl)propanamide and structurally relatedbis(fluorophenyl)alkylamides and acids (see, for example, FIGS. 1 and 2)in the preparation of a pharmaceutical formulation or composition foruse in a method of treating a pathology that is ameliorated by amodulation of CNS activity, whereby at least one symptom of saidpathology is alleviated. Thus, the present invention also contemplates atreatment method comprising the step of administering, to a patientsuffering from a pathology that is ameliorated by a modulation of CNSactivity, a therapeutically effective amount of a pharmaceuticalformulation comprising a pharmaceutically acceptable carrier and a novelcomposition selected from the aforementioned group of agents.

[0012] Pursuant to one embodiment of the invention, the treatedpathology is convulsions, an affective mood disorder, such as bipolarmood disorder, a neuropathic pain syndrome, a headache, such as amigraine headache, or a restlessness syndrome. For another embodiment,the pathology in question is ameliorated by a centrally mediateddecrease in muscle tone, and is illustrated by spasticity.

[0013] In accordance with another aspect of the present invention, a useis provided for the novel compositions of matter comprising3,3-bis(3-fluorophenyl)propanamide and structurally related amide andacid compounds in the preparation of a pharmaceutical formulation foruse in a method of treating a symptom of spasticity. By the same token,the present invention provides a method for alleviating a symptom ofspasticity in a subject in need of such treatment, comprising the stepof administering a therapeutically effective amount of one of the novelcompositions as described above.

[0014] Thus, in a preferred embodiment of the invention, a compound isprovided having the formula

[0015] wherein:

[0016] Y is independently selected from the group consisting of —H, —F,and —Cl;

[0017] X is either —NR¹R² or —OR¹;

[0018] R¹ is selected from the group consisting of —H, alkyl, andhydroxyalkyl;

[0019] R² is selected from the group consisting of —H, methyl, andethyl;

[0020] and n is either 0, 1, 2, 3, or 4. Preferably, R¹ is selected fromthe group consisting of -H, methyl, ethyl, isopropyl, isobutyl,tert-butyl, hydroxyisopropyl, and hydroxyethyl.

[0021] Thus, in another preferred embodiment of the invention, acompound is provided having the formula

[0022] wherein:

[0023] each F is independently in either the meta- or para-position;

[0024] R¹ is selected from the group consisting of —H, alkyl, andhydroxyalkyl;.

[0025] R² is selected from the group consisting of —H, methyl, andethyl;

[0026] and n is 0, 1, 2, 3, or 4. Preferably, R¹ is selected from thegroup consisting of —H, methyl, ethyl, isopropyl, isobutyl, tert-butyl,hydroxyisopropyl, and hydroxyethyl.

[0027] In a more preferred embodiment, a compound is provided having theformula

[0028] wherein:

[0029] n is 0, 1, or 2;

[0030] both F are either in the meta- or para-position;

[0031] R¹ is selected from the group consisting of —H, alkyl, andhydroxyalkyl; and

[0032] R² is selected from the group consisting of —H, methyl, andethyl. More preferably, R² is —H. More preferably, said compound isselected from the group consisting of compound 1, 2, 3, 7, 8, 9, 10, 11,12, 13, 14, and 15. In most preferred embodiments, said compound isCompound 1.

[0033] In other preferred embodiments of the invention, a method isprovided for treating a patient having a neurological disease ordisorder comprising administering a compound of the formula

[0034] wherein:

[0035] Y is independently selected from the group consisting of —H, —Fand —Cl;

[0036] X is either —NR¹R² or —OR¹;

[0037] R¹ is selected from the group consisting of —H, alkyl, andhydroxyalkyl;

[0038] R² is selected from the group consisting of —H, methyl, andethyl;

[0039] and n is either 0, 1, 2, 3, or 4. Preferably, R¹ is selected fromthe group consisting of —H, methyl, ethyl, isopropyl, isobutyl,tert-butyl, hydroxyisopropyl, and hydroxyethyl.

[0040] Thus, in another preferred embodiment of the invention, a methodis provided for treating a patient having a neurological disease ordisorder comprising administering a compound of the formula

[0041] wherein:

[0042] each F is independently in either the meta- or para-position;

[0043] R¹ is selected from the group consisting of —H, alkyl, andhydroxyalkyl;

[0044] R² is selected from the group consisting of —H, methyl, andethyl;

[0045] and n is 0, 1, 2, 3, or 4. Preferably, R¹ is selected from thegroup consisting of —H, methyl, ethyl, isopropyl, isobutyl, tert-butyl,hydroxyisopropyl, and hydroxyethyl. In a more preferred embodiment, amethod is provided for treating a patient having a neurological diseaseor disorder comprising administering a compound of the formula

[0046] wherein:

[0047] n is 0, 1, or 2;

[0048] both F are either in the meta- or para-position;

[0049] R¹ is selected from the group consisting of —H, alkyl, andhydroxyalkyl; and

[0050] R² is selected from the group consisting of —H, methyl, andethyl. More preferably, R² is —H. More preferably, the compound isselected from the group consisting of Compound 1, 2, 3, 7, 8, 9, 10, 11,12, 13, 14, and 15. In most preferred embodiments, said compound isCompound 1.

[0051] In other preferred methods, the neurological disease or disorderis selected from the group consisting of epilepsy, convulsions, andseizure disorders. In other preferred aspects, the treating of thepatient alleviates or prevents convulsions in said patient. In otherpreferred aspects, the neurological disease or disorder is associatedwith spasticity. In other preferred aspects, the neurological disease ordisorder is a neurodegenerative disorder. Preferably, said neurologicaldisease or disorder is selected from the group consisting of spasticity,skeletal muscle spasms, restless leg syndrome, anxiety, stress, multiplesclerosis, stroke, head trauma, spinal cord injury, Parkinson's Disease,Huntington's Disease, Alzheimers Disease, amyotrophic lateral sclerosis,migraine headaches, and bipolar disorder.

[0052] Other preferred embodiments of the invention include methods ofalleviating or preventing spasticity, or one or more symptoms ofspasticity, in a patient, comprising administering a compound of theinvention.

[0053] Also provided are pharmaceutical compositions, comprising acompound of the invention, and a pharmaceutically acceptable carrier.Preferably, the pharmaceutical composition comprises a compound selectedfrom the group consisting of Compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 13,14, and 15, and a pharmaceutically acceptable carrier. More preferably,the pharmaceutical composition comprises Compound 1.

[0054] Also provided in the present invention is a method for making atherapeutic agent comprising the steps of screening for said agent bydetermining whether said agent alleviates spasticity, and synthesizingsaid therapeutic agent in an amount sufficient to provide said agent ina therapeutically effective amount to a patient. Preferably, thetherapeutic agent comprises a compound of the invention.

[0055] Also provided in the present invention is a method for modulatingCNS activity comprising administering to a patient a compound of theinvention. Preferably, said modulation of CNS activity alleviates asymptom associated with convulsions, spasticity, an affective mooddisorder, a neuropathic pain syndrome, a headache, a restlessnesssyndrome, or a movement disorder.

[0056] Other objects, features, and advantages of the present inventionwill become apparent from the following detailed description. It shouldbe understood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the presentinvention, are given by way of illustration only, since various changesand modifications within the spirit and scope of the invention willbecome apparent to those skilled in the art from this detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

[0057]FIG. 1 depicts the structures and in vivo anticonvulsantactivities as assayed using the methods described herein, of3,3-bis(3-fluorophenyl)propanamide and several of its substitutedanalogs and congeners.

[0058]FIG. 2 depicts the structures of3,3-bis(3-fluorophenyl)propanamide and additional analogs and congeners.

[0059]FIG. 3 depicts the reduction in the flexor reflex in normalanesthetized rats elicited by Compound 1 in comparison to baclofen, asassayed using the methods described herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0060] 1. Overview

[0061] The inventors have discovered that3,3-bis(3-fluorophenyl)propanamide and certain of its pharmacologicallyactive analogs and congeners can be administered in vivo to effect amodulation of CNS activity. That is, these agents modulate CNS activity,by enhancing inhibitory, or decreasing excitatory, neurotransmissioncentrally, without complete suppression of all activity. Pursuant to thepresent invention, therefore, a subject who receives such an agent isnot overtly sedated, anesthetized, or paralyzed in the context of, forexample, decreasing seizures (no anesthesia), decreasing muscle tone (noparalysis), eliciting a calmative effect (no sedation), or amelioratingan ambulatory syndrome such as spasticity (no weakness or flaccidity).

[0062] A number of pathologies, exemplified by convulsions (seizures),spasticity, affective mood disorders, such as bipolar mood disorder,headaches (chronic, cluster, migraine) , restlessness syndromes,neuropathic pain, and movement disorders, have at least one symptom thatis alleviated by a modulation of CNS activity. Accordingly, anindividual who suffers from such a pathology is a candidate for therapythat entails, pursuant to the present invention, the individual'sreceiving a pharmaceutical formulation or composition containing3,3-bis(3-fluorophenyl)propanamide or one of its structurally relatedanalogs or congeners as one of the principal active ingredients.

[0063] 2. Exemplary Pathologies Ameliorated by a Modulation of CentralNervous System (CNS) Activity

[0064] CONVULSIONS: Epilepsy is a common disorder which has many causes,and it can be very difficult to control clinically, often requiringtreatment for many years to keep seizures under control. Researchershave stated that “[a]t this time, there is no satisfactory treatment forepilepsy in a substantial proportion of patients. Clinical trials haveshown that certain patients have a better response to one drug thananother, even when the patients have similar types of seizures and thedrugs have similar mechanisms of action. The frequency and severity ofside effects also varies substantially. Thus, multiple medications withdifferent mechanisms of action and attendant side effects will be neededfor treatment of epilepsy until either epilepsy can be cured or apotent, safe new drug with broad activity is discovered” and developed.Dichter et al., Drug Therapy 334:1583 (1996).

[0065] Due to the widespread availability of reasonably predictive andexperimentally accessible animal models of convulsant states, a numberof clinically useful anticonvulsants have been prepared and developed.For example, see Cereghino et al., “Introduction,” in ANTIEPILEPTICDRUGS, 4th ed., pages 1-11 (Raven Press 1995), which states: “In manypatients, seizures can be controlled with currently availableantiepileptic drugs, but 25 to 30 percent of patients continue to haveseizures despite optimal therapy, while many others experienceunacceptable side effects.” Dichter et al. (1996) supra.

[0066] Thus, many anticonvulsants in clinical use are plagued by theoccurrence of significant side effects, including troublesome daytimesedation, muscular weakness, tolerance, gingival hyperplasia, andpotentially fatal blood dyscrasias and hepatotoxicity. Many of theseside effects are especially of concern in the clinical management(treatment) of epilepsy in children.

[0067] The present invention can be used to treat convulsive disorderssuch as epilepsy. That is, the compositions and pharmaceuticalformulations and compositions of the invention display “anticonvulsantactivity,” which is evidenced by a reduction of the severity, number, orduration of convulsions in animal models of epilepsy. To alleviateconvulsions includes reducing the severity, number or duration ofconvulsions in a patient. Accordingly, the novel compositions andpharmaceutical formulations and compositions should be useful intreating conditions such as, but not limited to, generalizedtonic-clonic seizures, absence seizures, myoclonic seizures, simplepartial seizures, complex partial seizures, secondarily generalizedpartial seizures, status epilepticus, and trauma-induced seizures, asoccur following head injury or surgery.

[0068] SPASTICITY: Spasticity is a disorder characterized by an increasein tonic stretch reflexes (muscle tone) with exaggerated tendon jerksresulting from hyperexcitability of the stretch reflex. Lance, Symposiasynopsis, in SPASTICITY—DISORDERED MOTOR CONTROL, Feldman et al. (Eds.)(1980). Major disease states and conditions associated with spasticityinclude multiple sclerosis, cerebral palsy, stroke, trauma or injury tothe spinal cord, and head trauma. Symptoms that occur with spasticityinclude painful flexor and extensor spasms, increased or exaggerateddeep-tendon reflexes, clonus, muscular weakness, fatigue, lack ofdexterity, various degrees of loss of general motor function, paralysis,and impairment of sleep.

[0069] The pathological states observed in spasticity are fundamentallydifferent at the physiological level from the commonly experienced acutemuscular aches, strains, and sprains that occur from a localizedexternal insult to a particular muscle, i.e., outside of or peripheralto the CNS. These pathological states also are different from therelatively common involuntary spasms of smooth muscle, such as vascularspasms, bladder spasms, and bronchial spasms. Such non-spastic(non-CNS), peripheral or localized symptoms are commonly treated withso-called “antispasmodic” or “spasmolytic” agents, but these generallyare not useful in treating spasticity. Cedarbaum & Schleifer, “Drugs forParkinson's Disease, Spasticity and Acute Muscle Spasms,” in GOODMAN ANDGILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 8th ed. [hereafterGOODMAN AND GILMAN'S], pages 463-484 (Pergamon Press 1990).

[0070] The compositions of matter and pharmaceutical formulations andcompositions employed in accordance with the present invention caneffect a centrally mediated decrease in muscle tone and, hence, areuseful for the acute or chronic alleviation of one or more symptoms orside effects of spasticity. In this context, “spasticity” refers to aheightened tone of skeletal muscle which is manifested by symptoms suchas, but not limited to, painful flexor or extensor spasms, increased orexaggerated deep-tendon reflexes, hyperreflexia, loss of dexterity,muscular weakness, exaggerated tendon jerks, and clonus. The phrase“antispasticity agent” refers here to a composition that is useful forthe symptomatic treatment of spasticity, as demonstrated by thealleviation of at least one of the following manifestations or sideeffects of spasticity: painful flexor or extensor spasms, increased orexaggerated deep-tendon reflexes, hyperreflexia, loss of dexterity,muscular weakness, exaggerated tendon jerks, and clonus, or thereduction of the frequency of these manifestations or side effects.

[0071] Accordingly, the “alleviation” of spasticity refers here to thelessening of one or more symptoms of spasticity, including, but notlimited to, painful flexor or extensor spasms, increased or exaggerateddeep-tendon reflexes, hyperreflexia, loss of dexterity, muscle weakness,exaggerated tendon jerks, and clonus, or the reduction of the frequencyof these manifestations or side effects.

[0072] AFFECTIVE MOOD DISORDERS: These include conditions ranging fromdepression to dysphoric mania, for example, mania, schizoaffectivedisorder, traumatic brain injury-induced aggression, post-traumaticstress disorder, bipolar mood disorder, panic states, and behavioraldyscontrol syndromes. See Emrich et al., J. Affective Disorders8:243-250 (1985) and Bernasconi et al., in ANTICONVULSANTS IN AFFECTIVEDISORDERS, pages 14-32 (Excerpta Medica 1984). The novel compositionsand pharmaceutical formulations and compositions according to thepresent invention are effective in the treatment of these diseases,disorders, and conditions, and should exhibit improved side effectprofiles when compared to currently existing therapeutic agents in thistherapeutic category.

[0073] NEUROPATHIC PAIN SYNDROMES: Conditions in this category,involving “neuropathic pain,” affect a significant number of patientssuffering from disorders of the brain or spinal cord, such as stroke,trauma, multiple sclerosis, and diabetes. Casey, in PAIN AND CENTRALNERVOUS SYSTEM DISEASE (Raven 1991). The use of anticonvulsants to treatvarious pain states has been documented extensively. Swendlow, J. Clin.Neuropharmacol. 7: 51-82 (1984). Thus, a novel composition orpharmaceutical formulation or composition of the present invention canbe applied in similar fashion to ameliorate neuropathic pain.

[0074] HEADACHES: Headaches of the migraine type (Hering and Kuritzky,Cephalalgia 12:81-84 (1992) ), the cluster type (Hering and Kuritzky,loc. cit. 9:195-198 (1989)), and the chronic type (Mathew and Sabiha,Headache 31: 71-74 (1991)) have been treated with anticonvulsants. Thecompositions and formulations of the present invention can therefore beused to alleviate the symptoms associated with each of these threeheadache types, without the adverse side effects of current existingtherapies.

[0075] RESTLESSNESS SYNDROME: The phrase “restlessness syndrome” denotesa somatic (non-mental) restlessness characterized by involuntarymovement of the limbs, as well as by a sense of physical (rather thanmental) agitation, which is independent of mood and, hence, isdistinguished from restlessness per se. (See Sachev et al., Austral. NewZealand J. Psychiatry 30:38-53 (1996)).

[0076] Restlessness syndromes, inclusive of numerous indications, can beobserved in association with many organic and non-organic psychiatricillnesses. For example, drug-induced restlessness (tardive, chronic, andwithdrawal akathisias), such as drug-induced extrapyramidal symptoms, isone of the most common side effects of neuroleptic drug therapy. Alsowithin the restlessness-syndrome rubric are the so-called “restless legsyndrome” and “sleep-related periodic leg movements,” pathologies thatcan be associated with head and/or spinal cord trauma and with lesionsof the spinal cord. Idiopathic restless leg syndrome follows anautosomal dominant inheritance, with a variable clinical expression ofsymptoms. See O'Keefe, Arch. Intern. Med. 156: 243-248 (1996); Danek etal., in NEUROLOGICAL DISORDERS: COURSE AND TREATMENT, pages 819-823(Academic Press 1996); Mellick and Mellick, Neurology 45(suppl.):285-286 (1995). The present invention provides an effective therapy forrestlessness syndromes with minimal side effects.

[0077] MOVEMENT DISORDERS: Various agents are known to decrease thedyskinetic movement characterizing movement disorders such asParkinson's disease, Huntington's chorea, Alzheimer's disease, tardivedyskinesia, and stiff-man syndrome. Lloyd and Morselli, inPSYCHOPHARMACOLOGY: THE THIRD GENERATION OF PROGRESS (Raven Press 1987).A therapy within the present invention alleviates one or more symptomsof a movement disorder.

[0078] The compounds of the invention may also be useful asanxiety-reducing (anxiolytic) agents.

[0079] By “neurological disorder or disease” is meant a disorder ordisease of the nervous system including, but not limited to, epilepsy,anxiety, multiple sclerosis, strokes, head trauma, spinal cord injuries,and chronic neurodegenerative diseases such as Parkinson's andHuntington's diseases, Alzheimer's disease, and amyotrophic lateralsclerosis. Also meant by neurological disorder or disease“are thosedisease states and conditions in which an antispastic or anticonvulsantmay be indicated, useful, recommended, and/or prescribed.

[0080] By “neurodegenerative disease” is meant diseases such as, but notlimited to, Huntington's Disease, Parkinson's Disease, AlzheimersDisease, and amyotrophic lateral sclerosis (ALS).

[0081] By “anticonvulsant” is meant a compound capable of reducing theseverity, number, or duration of convulsions produced, observed, orfound in conditions such as generalized tonic-clonic seizures, absenceseizures, myoclonic seizures, simple partial seizures, complex partialseizures, secondarily generalized partial seizures, status epilepticus,and trauma-induced seizures, as occur following head injury or surgery.

[0082] By “anticonvulsant activity” is meant efficacy in reducing theseverity, number, or duration of convulsions produced, observed, orfound in conditions such as generalized tonic-clonic seizures, absenceseizures, myoclonic seizures, simple partial seizures, complex partialseizures, secondarily generalized partial seizures, status epilepticus,and trauma-induced seizures, as occur following head injury or surgery.

[0083] By “therapeutic dose” is meant an amount of a compound thatrelieves to some extent one or more symptoms of the disease or conditionof the patient. Additionally, by “therapeutic dose” is meant an amountthat returns to normal, either partially or completely, physiological orbiochemical parameters associated with or causative of the disease orcondition. Generally, it is an amount between about 0.1-15-20-30 mg/kgbody weight, depending on the age, size, and disease associated with thepatient. The dosing can be one to four times a day.

[0084] By “pharmaceutical composition” is meant a therapeuticallyeffective amount of a compound of the present invention in apharmaceutically acceptable carrier, i.e., a formulation to which thecompound can be added to dissolve or otherwise facilitate administrationof the compound. Examples of pharmaceutically acceptable carriersinclude water, saline, and physiologically buffered saline. Such apharmaceutical composition is provided in a suitable dose. Suchcompositions are generally those which are approved for use in treatmentof a specified disorder by the FDA or its equivalent in non-U.S.countries.

[0085] By “patient” is meant any animal that presents a symptom that canbe alleviated by the administration of an anticonvulsant or antispasticcomposition. Preferably, the animal is a mammal. Most preferably, theanimal is a human.

[0086] By “alkyl” is meant a branched or unbranched hydrocarbon chaincontaining between 1 and 6, preferably between 1 and 4, carbon atoms,such as, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, 2-methylpentyl, cyclopropylmethyl, allyl, andcyclobutylmethyl.

[0087] By “lower alkyl” is meant a branched or unbranched hydrocarbonchain containing between 1 and 4 carbon atoms, of which examples arelisted herein.

[0088] By “hydroxyalkyl” is meant an alkyl group as defined above,substituted with a hydroxyl group.

[0089] 3. Methods for Preparing Pharmaceutical Formulations andCompositions

[0090] As demonstrated herein, useful compounds of this invention andtheir pharmaceutical compositions may be used to treat neurologicaldisorders or diseases. While these compounds will typically be used intherapy for human patients, they may also be used to treat similar oridentical diseases in other vertebrates such as other primates, domesticanimals, farm animals such as swine, cattle, and poultry, and sportsanimals and pets such as horses, dogs, and cats.

[0091] The pharmaceutical formulations and compositions of the presentinvention can be prepared according to known methods to preparepharmaceutically useful compositions, whereby active agents are combinedin a mixture with a pharmaceutically acceptable carrier. For instance,see Gennaro (Ed.), REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ed. (MackPublishing Co. 1990) and GOODMAN AND GILMAN'S, cited above. Acomposition is said to be in a “pharmaceutically acceptable carrier” ifits administration can be tolerated by a recipient patient. Sterilephosphate-buffered saline is one example of a pharmaceuticallyacceptable carrier. Other suitable carriers (e.g., saline and Ringer'ssolutions) are well known to those skilled in the art. See, for example,REMINGTON'S PHARMACEUTICAL SCIENCES, supra.

[0092] Pharmaceutically acceptable salts are generally well known tothose of ordinary skill in the art, and may include, by way of examplebut not limitation, acetate, benzenesulfonate, besylate, benzoate,bicarbonate, bitartrate, calcium edetate, camsylate, carbonate, citrate,edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate,napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/disphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, or teoclate, otherpharmaceutically acceptable salts may be found in, for example,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.(18th ed. 1990).

[0093] Preferred pharmaceutically acceptable salts include, for example,acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide,hydrochloride, maleate, mesylate, napsylate pamoate (embonate),phosphate, salicylate, succinate, sulfate, or tartrate.

[0094] The useful compounds of this invention may also be in the form ofpharmaceutically acceptable complexes. Pharmaceutically acceptablecomplexes are known to those of ordinary skill in the art and include,by way of example but not limitation, 8-chlorotheophyllinate (teoclate).

[0095] The pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

[0096] In general, the dosages of the anticonvulsant and antispasticityagents described herein will vary depending upon such factors as thepatient's age, weight, height, sex, general medical condition, andprevious medical history. For purposes of therapy, a compound of thepresent invention and a pharmaceutically acceptable carrier areadministered to a subject in need of such treatment in a therapeuticallyeffective amount. The combination of active agent and carrier is said tobe administered in a “therapeutically effective amount” if the amountadministered is physiologically significant. An agent is physiologicallysignificant if its presence results in a detectable change in thephysiology of a recipient patient. In the present context, for example,the anticonvulsant agent is physiologically significant if the presenceof the agent results in the reduction of the severity, number, orduration of convulsions, while an antispasticity agent isphysiologically significant if the presence of the agent results in thealleviation of one or more symptoms of spasticity.

[0097] The compositions and formulations of the present invention can beadministered orally using solid oral dosage forms such as, for example,enteric-coated tablets, caplets, gelcaps, sprinkles, or capsules, or vialiquid oral dosage forms such as syrups or elixirs. The indicated dosageof 3,3-bis(3-fluorophenyl)propanamide and structurally relatedbis(fluorophenyl)alkylamide compounds as anticonvulsants is on the orderof 1-1000 mg per dose, and preferably 10-500 mg per dose. Unit solidoral dosage forms preferably contain about 10-250 mg per tablet orcapsule, which should preferably be taken 1-2 at a time for a maximum oftwo times per day, at a dosage of about 0.1-15 mg/kg body weight. Liquidformulations can also be employed with active ingredient compositions soas to provide 1-2 teaspoonfuls per dose. Furthermore, correspondingreduced dosage pediatric chewable and liquid oral dosage forms can alsobe administered. These compounds also can be added to foods andbeverages in the form of drops (with a dropper from a “concentrate”preparation) for oral administration. In addition, the compounds of theinvention may be formulated into chewing gum to facilitate oral deliveryand absorption.

[0098] Alternatively, the compounds of the invention can be administeredby injection or other systemic routes, such as transdermal ortransmucosal administration, for example, nasally, buccally, orrectally, via suppositories or using sublingual, vaginal, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, and/or intramedullary injections, as well as intrathecal,direct intraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections. Oral administration is much more convenient,however, and therefore is preferred.

[0099] For use in an oral antispasticity formulation or composition, thedosage level of active ingredient(s) is on the order of 1-1000 mg perdose, and preferably, 10-250 mg per dose, or 0.1-15 mg/kg body weight.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition. (Seee.g. Fingl et al., in The Pharmacological Basis of Therapeutics, 1975,Ch. 1, p. 1).

[0100] It should be noted that the attending physician would know howand when to terminate, interrupt, or adjust administration due totoxicity or organ dysfunction. Conversely, the attending physician wouldalso know to adjust treatment to higher levels if the clinical responseswere not adequate (precluding toxicity). The magnitude of anadministered dose in the management of the disorder of interest willvary with the severity of the condition to be treated and to the routeof administration. The severity of the condition may, for example, beevaluated in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

[0101] For injection, the agents of the invention may be formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hank's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art.

[0102] Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

[0103] In addition to a use in humans, the compounds of the inventioncan be used in veterinary applications, for example, as anticonvulsantagents, anxiolytic agents, or -antispasticity agents, in animals such ascats, dogs, birds, horses, cattle, mink, poultry, and fish. In suchcases, the active compound(s) may be administered by injection or othersystemic routes, such as transdermal or transmucosal administration (forexample, rectal administration via suppositories), or orally by additionto food or drink. As an anticonvulsant agent, the indicated oral dosageof the compounds of the invention per kilogram of body weight of suchanimals is about 1-1000 mg/kg, depending upon the species of animal andthe route of administration. A preferred range for oral dosage is about10-500 mg/kg body weight.

[0104] The indicated oral dosage of the compounds of the invention perkilogram body weight as antispasticity agents for animals is in therange of about 1-1000 mg/kg, depending upon the species of animal andthe route of administration. A preferred range for oral dosage is about5-500 mg/kg body weight.

[0105] The present invention thus contemplates a variety ofpharmaceutical compositions containing the compounds of the invention asactive ingredients that are suitable for oral, parenteral, transdermal,transmucosal, intranasal, buccal, or rectal administration.

[0106] It is further understood that the compounds of the invention canbe used in combination with other pharmaceutically active ingredients.

[0107] 4. Demonstrating Therapy-Implicating Activity

[0108] The suitability and effectiveness of a given compound,pharmaceutical formulation, or composition for the alleviation of apathology, as discussed above, can be demonstrated using appropriateanimal models such as (but not limited to) those described below.

[0109] (a) Anticonvulsant Activity

[0110] Methods for determining and evaluating the in vivo anticonvulsantactivity of test compounds in experimental animals (e.g., rodents) arewell known in the art (Foye, W. O. (Ed.), Principles of MedicinalChemistry, 3rd ed. (1989) Lea and Febiger, Philadelphia, Pa., pp.173-178; Gilman, A. G., et al., Goodman and Gilman's The PharmacologicalBasis of Therapeutics, 9th ed. (1996) Pergamon Press, New York, pp.461-486; Wolff, M. E., Burger's Medicinal Chemistry, 5th ed. (1996),Wiley-Interscience, New York, pp. 182-198. Relevant animal modelsinclude the Frings audiogenic seizure-susceptible mouse and the rat MES(Maximal Electroshock) assays. Both of these assays were used to assessthe anticonvulsant properties of the test compounds. For general methodsand terminology relating to anticonvulsant assays, see J. A. Vida,“Anticonvulsants,” in W. O. Foye et al. (Eds.), Principles of MedicinalChemistry, 4^(th) Ed. (1995) pp. 182-198.

[0111] There are numerous in vivo models involving different kinds ofseizures and behavioral effects that are relevant for clinicallydistinct forms of epilepsy. It therefore is useful to test for effectsin more than one model.

[0112] Loscher and Schmidt (Epilepsy Research 17:95-134, 1994) proposeda test hierarchy in various animal models of epilepsy for thepharmacologic evaluation of antiepileptic drugs. A more detaileddescription of these various models as well as the possible correlatesto human epilepsy can be found in reviews by H. S. White (inAntiepileptic Drugs, Fourth Edition, edited by R. H. Levy, R. H.Mattson, and B. S. Meldrum, Raven Press, Ltd., New York, 1995, pp99-110) and H. Kupferberg (Epilepsia 30 (Suppl 1): S51-S56, 1989).

[0113] One useful model is provided by the Frings audiogenicseizure-susceptible mouse, a model of reflex epilepsy. The Fringsaudiogenic seizure-susceptible mouse is a genetic mouse model ofepilepsy used to indicate a preliminary, general level of efficacy andtherapeutic potential, but is not predictive of any particular humanseizure disorder. Compounds are measured for their ability to blocksound-induced tonic extension seizures (White et al., 1995). At the timeof testing, individual mice are placed into a round Plexiglas chamberand exposed to a sound stimulus of 110 decibels, 11 kHz, for 20 seconds.Animals not displaying tonic hindlimb extensions are consideredprotected. In addition, the seizure score for each mouse can be recordedas: (1) running for less than 10 seconds; (2) running for greater than10 seconds; (3) clonic activity of limbs and/or vibrissae; (4) forelimbextension/hindlimb flexion; and (5) hindlimb extension.

[0114] The average seizure score can be calculated for each group ofmice employed in the dose-response study. At each dose, mice are alsotested on a rotarod for testing of motor impairment (“toxicity”).Testing for motor impairment on the rotarod involves placing a mouse fora three-minute period on a one-inch diameter rod and rotating at sixrevolutions per minute. If the mouse falls off of the rotating rod threetimes within the three-minute period, it is considered a toxic response.

[0115] b) The Maximal Electroshock Seizure (MES)Test

[0116] The Maximal Electroshock Seizure (MES) Test is a highlypredictive animal seizure model of human generalized tonic-clonicseizures. In the MES test, a 60-Hz alternating current is delivered for0.2 sec through corneal electrodes in mice. Abolition of the hind-limbtonic extensor component is taken as the endpoint for this test. Absenceof this component suggests that the test substance has the ability toprevent the spread of seizure discharge through neural tissue (White etal., 1995)

[0117] c) The Acute/Chronic Spinally Transected Rat and the AcuteDecerebrate Rat

[0118] There are several models of spasticity, including the acutedecerebrate rat, the acute or chronic spinally transected rat, and thechronically spinal cord-lesioned rat. (See, e.g., Bertman and Adkovat,Brain Res. 684:8-18 (1995); Chen et al., Neuroscience 23:641-647(1987)). The acute models, although of proven value in elucidating themechanisms involved in the development of spasticity, have come undercriticism due to the fact that they are acute.

[0119] The animals usually die or have total recovery from spasticity.The spasticity develops immediately upon intervention, unlike thespasticity that evolves in the human condition of spasticity, which mostoften initially manifests itself as a flaccid paralysis. Only afterweeks and months does spasticity develop in humans. Some of the morechronic-lesioned or spinally transected models of spasticity dopost-operatively show flaccid paralysis. At approximately four weekspost-lesion/transection, the flaccidity changes to spasticity ofvariable severity.

[0120] Although all of these models have their own particulardisadvantages and lack of true representation of the human spasticcondition, they have provided much information about the nature ofspasticity. These models have also provided methods to test varioustreatment paradigms that have led to similar treatments being tested inhumans. Many of these models have also made use of different species,such as cats, dogs, and primates.

[0121] Baclofen, diazepam (Valium), and tizanidine are effective ondifferent parameters of spasticity (EMG recordings, H-reflex, the H/Mratio, mono- and polysynaptic reflexes, clonus, hyperreflexia) in thesemodels. The flexor reflex is a polysynaptic response elicited bystimulation of the bottom of the foot and models the withdrawal reflex.Compounds such as baclofen, the benzodiazepines, tizanidine, and NMDAreceptor antagonists have been shown to reduce the flexor reflex inrodents (normal or spinally transected) and are also effectiveantispastics in humans (Bertman and Advokat, 1995; Hao, 1990; Young,1994; Davidoff, 1985).

[0122] (d) Primary Observation Irwin Test in the Rat

[0123] This method is based on that described by Irwin,Psychopharmacologia 13: 222-257 (1968) It is used to detectphysiological, behavioral, and toxic effects of a test substance, andindicates a range of dosages that can be used for later experiments.Typically, rats (three per group) are administered the test substanceand are then observed in comparison with a control group given vehicle.Behavioral modifications, symptoms of neurotoxicity, pupil diameter, andrectal temperature are recorded according to a standardized observationgrid derived from that of Irwin. The grid contains the following items:mortality, sedation, excitation, aggressiveness, Straub tail, writhes,convulsions, tremor, exophthalmos, salivation, lacrimation,piloerection, defecation, fear, traction, reactivity to touch, loss ofrighting reflexes, sleep, motor incoordination, muscle tone,stereotypies, head-weaving, catalepsy, grasping, ptosis, respiration,corneal reflex, analgesia, abnormal gait, forepaw treading, loss ofbalance, head twitches, rectal temperature, and pupil diameter.Observations are performed at 15, 30, 60, 120, and 180 minutes followingadministration of the test substance, and also 24 hours later.

[0124] (e) Rotarod Test in the Rat and Mouse

[0125] This is a test of neurological deficits using the methoddescribed by Dunham et al., J. Am. Pharm. Assoc. 46: 208-209 (1957) Ratsor mice are placed on a rod rotating at a speed of six to eight turnsper minute. The number of animals which drop off of the rod before threeminutes is counted and the drop-off times are recorded (maximum: 180sec). Eight to ten rats are studied per group and the test is performedblind. The test compound is administered i.p. 60 min prior to testing.Diazepam (Valium), a benzodiazepine, is administered at 8 mg/kg, i.p.,as the reference substance. A control group administered the vehicle isalso included in the study.

[0126] (f) Anti-Manic Activity

[0127] To assess the possible use of compounds in the treatment ofaffective mood disorders, such as bipolar mood disorder, one can employthe amphetamine-induced hyperactivity model in rats. In addition tobeing a test for classical and atypical antipsychotic activity, thisprocedure has also been proposed as a simple animal model of manicbehavior. Costall et al., Brain Res. 123: 89-111 (1977).

[0128] (g) Neurogenic Inflammation of the Meninges

[0129] Neurogenic inflammation within the meninges has been proposed asan event in the underlying pathology of migraine headaches. Lee et al.,Brit J. Pharmacol. 116: 1661-1667 (1995). Compounds are tested for theirability to block the leakage of radiolabeled bovine serum albumin withinthe dura mater post trigeminal stimulation.

[0130] (h) Analgesic Properties

[0131] There are many whole-animal assays for determining analgesicproperties, such as writhing, hot-plate, tail-flick, arthritic pain, pawpressure tests, and the Bennet or Chung models of neuropathic pain.Albe-Fessard et al., in ADVANCES IN PAIN RESEARCH AND THERAPY 13, pages11-27 (Raven Press 1990).

[0132] (i) Therapeutic Benefit Relative to Movement Disorders andRestlessness Syndromes

[0133] Animal models exist for the study of movement disorders andrestlessness syndromes, for example, drug-induced akathisias, serotoninsyndrome, and rotation induced by unilateral nigral lesions. Lloyd andMorselli (1987), supra. Additionally, individual case reports ofanecdotal efficacy of compounds in humans have been a source for supportfor these indications. Mellick and Mellick (1995), supra; Olson et al.,Am. J. Med. 102: 60-66 (1997).

[0134] Anxiolytic activity of the compounds of the invention can bedemonstrated using appropriate methods known in the art, such as thosedescribed in Balandrin et al., U.S. Pat. No. 5,506,268 (1996).

[0135] The therapeutic effects of the compounds of the invention invarious of the assays described above, combined with a general lack oftoxicity, make the compounds of the present invention ideal agents forthe treatment of the pathologies described above, includingconvulsions/seizures (epilepsy) and spasticity. With this background,the present invention will be understood more readily by reference tothe following examples, which are provided for purposes of illustrationand are not intended to be limiting of the invention.

[0136] Although the foregoing refers to particular preferredembodiments, it will be understood that the present invention is not solimited. It will occur to those of ordinary skill in the art thatvarious modifications may be made to the disclosed embodiments and thatsuch modifications are intended to be within the scope of the presentinvention, which is defined by the claims below.

[0137] All publications mentioned in this specification are indicativeof the level of skill of those in the art to which the inventionpertains. All publications are herein incorporated by reference to thesame extent as if each individual publication were specifically andindividually indicated to be incorporated by reference in its entirety.

EXAMPLES Example 1

[0138] Anticonvulsant Activity

[0139] Desired properties of an anticonvulsant drug include: the drugcan be administered by oral or injectable routes, the drug exhibitseffective anticonvulsant activity against several seizure types,including, but not limited to, generalized tonic-clonic seizures,absence seizures, myoclonic seizures, simple partial seizures, complexpartial seizures, secondarily generalized partial seizures, statusepilepticus, and trauma-induced seizures, as occur following head injuryor surgery; and the drug is devoid of or has minimal side effects suchas impairment of cognition, disruption of motor performance, sedation orhyperexcitability.

Example 2

[0140] Synthesis of Compounds

[0141] Capillary gas chromatographic and low-resolution mass spectraldata were obtained using a Hewlett-Packard (HP) 5890 Series II GasChromatograph coupled to an HP 5971 Series Mass Selective Detector[Ultra-2 Ultra Performance Capillary Column (cross-linked 5% PhMesilicone); column length, 25 m; column i.d., 0.20 mm; Helium flow rate,60 mL/min; injector temp., 250° C.; temperature program, 20° C./min from125to 325° C. for 10 min, then held constant at 325° C. for 6 min].

[0142] Thin-layer chromatography was performed using Analtech Uniplate250-μm silica gel HF TLC plates. UV light in conjunction with ninhydrinand Dragendorff's spray reagents (Sigma Chemical Co.) were used fordetecting compounds on the TLC plates. Most reagents used in reactionswere purchased from the Aldrich Chemical Co. (Milwaukee, Wis.), SigmaChemical Co. (Saint Louis, Mo.), Fluka Chemical Corp. (Milwaukee, Wis.),Fisher Scientific (Pittsburgh, Pa.), TCI America (Portland, Oreg.), orLancaster Synthesis (Windham, N.H.).

[0143] Preparation of 4,4-bis(4-fluorophenyl)butanamide (Compound 12)

[0144] (a) Preparation of 1-acetoxy-4,4-bis(3-fluorophenyl)butane

[0145] A solution of chloride (20.0 g, 71.2 mmol) in DMF (50 mL) andpotassium acetate (14.0 mg, 142 mmol) was heated to 140° C. for 60 min(start time 12:36 min). Cooled to 25° C., poured into 200 mL sat. NaCl,and extracted product with EtOAc (2×100 mL), washed EtOAc layer withsat. NaCl (3×100 mL), dried (Na₂SO₄) , and evaporated under vacuum toprovide 19.43 g, 89.8% yield of an orange oil.

[0146] (b) Preparation of 4,4-bis(3-fluorophenyl)-1-butanol

[0147] A solution of the ester (19.4 g, 63.9 mmol) in abs. EtOH (250 mL)and 10N NaOH (6.4 mL, 64 mmol) was heated to reflux for 60 min. Thesolvent was then evaporated under vacuum. The residue was dissolved inEtOAc (200 mL), sat. NaCl (100 mL), and H₂O (10 mL). The layers wereseparated and the organic layer was washed with sat. NaCl (3×50 mL) ,dried (anhyd. Na₂SO₄), and evaporated under vacuum to provide 15.4 g,92.2% yield of an oil. TLC (Hex/EtoAc, 3:1), Rf=0.23.

[0148] (c) Preparation of 4,4-bis(3-fluorophenyl)butyric Acid

[0149] Chromium trioxide (27.9 g, 279 mmol) was dissolved in H₂O (42 mL)and was cooled in an ice bath. Conc. H₂SO₄ (24 mL) was added withshaking. This suspension was added dropwise to a solution of the alcohol(15.4 g, 55.8 mmol) in acetone over 10 min. Stirred vigorously for 15min then H₂O (200 mL) was added and the product was extracted with EtOAc(2×100 mL). The organic layer was washed with H₂O (2×50 mL), dried(Na₂SO₄), and evaporated under vacuum to provide 14.0 g, 90.7% of agreenish glass. This material was chromatographed on silca gel (50×300mm) elution with CHCl₃ (1 L), 3% MeOH/CHCl₃ (0.5 L), then Hex/EtOAc[1:1] (1 L) to provide 10.3 g, 67.1% of carboxylic acid as a viscousoil: GC/MS: Rt=7.56 min. m/z 276.

[0150] (d) Preparation of 4,4-bis(3-fluorophenyl)butyrylchloride

[0151] A mixture of the carboxylic acid (10.3 g, 37.5 mmol) and thionylchloride (8.20 mL, 112 mmol) was heated to 85° C. in an oil bath withvigorous stirring for 6 h. The solution was then cooled to roomtemperature and excess thionyl chloride was removed by rotaryevaporation (1 h, 1 mm Hg, 100° C.) and the residual thionyl chloridewas azeotroped with benzene (2×100 mL). This procedure povided the acidchloride as a liquid, 10.5 g, 95.1%.

[0152] (e) Preparation of 4,4-bis(3-fluorophenyl)butanamide

[0153] A solution of the acid chloride (1.75 g, 5.94 mmol) in EtOAc (50mL) was added dropwise over a period of 15 min to a vigorously stirringsolution of conc. aq. NH₄OH (2.1 mL, 17.8 mmol, 3 equivt) in H₂O (50mL). The biphasic mixture was then stirred for 1 h at room temperature.The organic layer was separated and washed with 1 M HCl (3×25 mL), 1 MNaOH (2×30 mL), and sat. aq. NaCl (2×25 mL). The organic layer was thenfiltered, dried (anhyd. Na₂SO₄), filtered again, and the solvent wasremoved under vacuum to provide crude product as an oil whichcrystallized on standing. This material was chromatographed on silicagel, elution with hex/EtOAc [1:1] followed by 5% MeOH/CHCl₃; fractionscontaining product where pooled and evaporated under vacuum to provide1.13 g, 72.3% yield of amide as a colorless oil which crystallized onstanding. TLC Hex/EtOAc [1:1], Rf 0.23; GC/EIMS, Rt=64 min m/z 263.

[0154] Preparation of 4,4-bis(3-fluorophenyl)butanamide (Compound 11)

[0155] (a) Preparation of3,3-bis(3-fluorophenyl)-3-hydroxypropylchloride

[0156] Cerium chloride heptahydrate (81.8 g, 220 mmol, 3.0 equivt) wasfinely ground in a mortar then placed in a 1-L flask and was heated in avacuum oven at 130° C. and 0.1 mm Hg for 18 h. The anhydrous ceriumchloride was then suspended in THF (400 mL). Ethyl 3-chloropropionate(10.0 g, 73.2 mmol) was then added and the reaction mixture was stirredat room temperature for 1 h. The mixture was then cooled in an ice bathand stirred for 30 min at 0° C.

[0157] Meanwhile, the Grignard reagent was prepared as follows. In a 500mL, 3-necked flask, to a suspension of Mg (5.34 g, 220 mmol) in THF (320mL) was added {fraction (1/20)} of bromofluorobenzene (39.7 g, 227 mmol)with I₂ (1 crystal). The reaction mixture was heated to reflux. Afterinitiation, the rest of the bromide was added dropwise over a period of10 min. The reaction was then refluxed for 30 min. The solution wascooled to 0° C. in an ice bath and transferred via canula to the mixtureof cerium chloride and ester in THF over a period of 20 min. Thereaction was stirred for 1 h at 0° C., then 1 h at room temperature.After 1 h at room temperature, it was cooled in an ice bath, 10% aq. HCl(250 mL) was added, and the layers separated. The lower aqueous layerwas washed with CHCl₃ (2×100 mL). The organic layers were combined andevaporated under vacuum to yield 22.3 g, 108% of a green-brown oil.

[0158] (b) Preparation of 3,3-bis3-fluorophenyl)2-propenylchloride

[0159] A solution of 22.3 g, 78.9 mmol of tertiary alcohol was stirredat 100° C. with conc. HCl (200 mL) for 1 h. The reaction was then cooledand diluted with H₂O (300 mL). The mixture was extracted with CHCl₃(4×50 mL) and evaporated under vacuum to provide crude product. Thismaterial was chromatographed on a 50×300 mm silica column (elution withHex/EtOAc (30:1), then [20:1]). Fractions containing product werecombined and evaporated to provide 11.4 g (54% yield) of product as acolorless oil.

[0160] (c) Preparation of 4,4-bis(3-fluorophenyl)-3-butenenitrile

[0161] 6.94 g, 26.2 mmol of chloride was dissolved in EtOH (100 mL). KCN(17.1 g, 262 mmol, powdered) was added and the reaction mixture wasrefluxed. After 3 h, the volatiles were evaporated under vacuum. Theresidue was dissolved in diethyl ether (100 mL), washed with H₂O (3×25mL), dried (anhyd. Na₂SO₄), and evaporated to provide the crude product.Chromatography on silica gel (50×300 mm) Hex/EtOAc [10:1] provided 5.05g, 75.6% yield of a yellow oil. TLC (Hex/EtOAc, [10:1]) Rf=0.32.

[0162] (d) Preparation of 4,4-bis(3-fluorophenyl)-3-butylnitrile

[0163] 5.05 g, 19.8 mmol of alkene was dissolved in EtOH (100 mL). 10%Pd/C was added and the mixture was hydrogenated on a Parr apparatus at25° C., 60 psig. After shaking for 0.5 h, the mixture was filteredthrough Celite and the filtrate was evaporated under vacuum to yield 4.5g (88.4%) of a colorless oil.

[0164] (e) Preparation of 4,4-bis(3-fluorophenyl)butanamide

[0165] The nitrile (4.50 g, 17.5 mmol) was dissolved into conc. H₂SO₄(10 ML). The reaction solution was then stirred for 30 min at roomtemperature. The reaction was then heated to 50° C. in an oil bath.After 1.75 h at 50° C., the reaction solution was poured onto a mixtureof ice/water (100 mL). The solution was extracted with hot EtOAc (8×100mL), dried (Na₂SO₄), and evaporated under vacuum to provide crudeproduct as a thick oil. This material was chromatographed on silica gel(50×300 mm, elution with 5% MeOH/CHCl₃) and rechromatographed with 3%MeOH/CHCl₃. Evaporation of the fraction containing product provided0.771 g, 16.0% of a white powder.

[0166] Synthesis of 3,3-bis(3-fluorophenyl)propanamide (Compound 1)

[0167] (a) Preparation of ethyl 3,3-bis(3-fluorophenyl)acrylate

[0168] A suspension (under argon) of sodium hydride (3.63 g, 151.2 mmol)in dimethylformamide (DMF, 500 mL) was treated dropwise with a solutionof triethyl phosphonoacetate (37.0 g, 165.0 mmol) in DMF (200 mL). Thereaction was heated at 65 EC for 2 hr. After this time the reaction wascooled to 0° C. and treated with a solution of 3.3′-difluorobenzophenone(30.0 g, 137.5 mmol) in DMF (200 mL).

[0169] The reaction was stirred at ambient termperature for 16 hr. Thereaction was quenched by the addition of water (1 L) and equilibratedwith hexane-ethyl acetate (1:1, 2 L) . The aqueous phase was separatedand washed one additional time with hexane-ethyl acetate (1:1, 2 L). Theorganic phases were combined, washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated to afford 38.81 g (98%) of the titlecompound as a clear, colorless oil. GC/EI-MS analysis gave a singlecomponent Rt=6.38 min, m/z (rel.int.) 288 (M+,11), 259 (8), 243 (54),214 (100), 194 (53), 175 (30), 123 (38) 120 (48) , 94 (38), and 75 (74).

[0170] (b) Preparation of ethyl 3,3-bis(3-fluorophenyl)propionate

[0171] A solution of ethyl 3,3-bis(3-fluorophenyl)acrylate (38.81 g,134.8 mmol) in absolute ethanol (300 mL) was hydrogenated in thepresence of palladium hydroxide on carbon (5 g wet, Degussa type) at 60p.s.i. H₂ for 30 min at ambient temperature. After this time thereaction was filtered and concentrated to afford 39.08 g (100%) of thetitle compound as a clear, colorless oil. GC/EI-MS analysis gave asingle component: Rt=6.21 min, m/z (rel.int.) 290 (M+,6), 262 (1), 244(5), 216 (100), 203 (67), 201 (48), 183 (63), 101 (41), 96 (17), and 75(25).

[0172] (c) Preparation of 3,3-bis(fluorophenyl)propionic Acid

[0173] A solution of ethyl 3,3-bis(3-fluorophenyl)propionate (39.08 g,134.8 mmol) in absolute ethanol (500 mL) was treated with 5N NaOH (500mL) and stirred at ambient temperature for 16 hr. After this time thereaction mixture was concentrated (removal of ethanol) on a rotaryevaporator and diluted with water (1 L). The aqueous mixture was washedonce with diethyl ether (500 mL) and the remaining aqueous mixtureacidified (pH-1) by the addition of concentrated HCl. The aqueous phasewas extracted with methylene chloride (4×250 mL). The combined organicextracts were dried over anhydrous MgSO₄, filtered, and concentrated toafford 31.76 g (90%) of the title compound as a white solid. GC/EI-MSanalysis gave a single component: Rt=6.60 min, m/z (rel. int.) 262 (M+,13), 243 (1), 216 (40), 203 (85), 201 (54), 183 (100), 170 (11) , 121(31), 101 (43), 96 (24), and 75 (45).

[0174] (d) Preparation of 3,3-bis(3-fluorophenyl)propanamide

[0175] 3,3-Bis(3-fluorophenyl)propionic acid (31.31 g, 119.5 mmol) wasdissolved in thionyl chloride (100 mL) and heated at reflux for 16 hr.After this time the excess thionyl chloride was removed by distillationand the remaining oil, the acid chloride product, dissolved indichloromethane (200 mL). The solution of acid chloride was addeddropwise to a stirred solution (−78° C.) of ammonia (35 mL) indichloromethane (500 mL), followed by the addition of pyridine (100 mL)The reaction was stirred at rt for 1 h and quenched with 10% HCl (500mL). After equilibration, the aqueous phase was removed and theremaining organic phase was washed with 10% HCl (3×500 mL). The organicphase was dried over anhydrous MgSO₄, filtered, and concentrated to asolid. The solid was dissolved in diethyl ether (1 L) and washed with 1NNaOH (4×500 mL), 10% HCl (3×500 mL), and brine (500 mL). The organicsolution was dried over anhydrous MgSO₄, filtered, and concentrated to asolid (28.24 g). Recrystallization of this material from hot toluene(100 mL, washing with 100 mL of 0° C. toluene) gave 25.39 g (81%) of thetitle compound as a white, crystalline solid: m.p. 103-105° C.; GC/EI-MSanalysis gave a single component at Rt=7.43 min, m/z (rel. int.) 261(M+, 15), 244 (2), 216 (27) , 203 (25), 201 (41), 183 (57), 170 (7), 164(9), 149 (8), 133 (6), 121 (52), 111 (15) , 109 (20), 101 (41), 96 (27),95 (24), 75 (42), and 44 (100).

[0176] Synthesis of N-tert-butyl-3,3-bis(3-fluorophenyl)propanamide(Compound 5)

[0177] To a −78° C. solution of the acid chloride (5 g, 17.8 mmol [15.5mmol actual]) in CH₂Cl₂ (50 mL) was added in a stream t-butyl amine (5.6mL, 3.91 g, 53.5 mmol, 3 equivt) The dry-ice bath was removed and thereaction mixture was then stirred for 4 h at room temperature. Themixture was then poured into diethyl ether (100 mL) and the organiclayer was washed with 1 M HCl (4×50 mL), 1 M NaOH (3×50 mL), and H₂O(3×50 mL). The organic layer was then filtered (paper), dried (anhydr.Na₂SO₄), filtered again, and the solvent was removed under vacuum toprovide 4.34 g, 93% of product as a cream-colored powder. TLC analysis:Hex/EtOAc [3:1], showed one major spot. This material was recrystallizedfrom abs. EtOH/H₂O [1:1] (100 mL) plus abs. EtOH (10 mL, to dissolve) toprovide 3.59 g, 76.7% yield of product as light-straw-colored needles.TLC Hex/EtOAc [1:1], Rf=0.76; GC/EIMS, Rt=7.55 min, m/z 317.

[0178] Synthesis of 3.3-bis(4-fluorophenyl)propanamide (Compound 10)

[0179] (a) Preparation of 3,3-bis(4-fluorophenyl)acrylonitrile

[0180] Using a nitrogen atmosphere, to a solution of diethylcyanomethylphosophonate (8.52 g, 48.1 mmol) dissolved in DMF (100 mL)was added NaH (2.02 g, 50.4 mmol, 60% dispersion in mineral oil) inportions over a period of 5 min. The reaction was stirred at 25° C. for15 min. Difluorobenzophenone (10 g, 45.8 mmol) then was added and thereaction was stirred 18 h at room temperature. The reaction mixture wasthen poured in H₂O (400 mL) and extracted with CHCl₃ (7×100 mL). Thecombined organic layers were evaporated in vacuo and the residue wasredissolved in diethyl ether (150 mL). The ether layer was washed withbrine (3×100 mL), dried (anhyd. Na₂SO₄), and evaporated under vacuum toprovide 9.53 g, 86.3% of crude product as a light-purple solid. GC/EIMSRt=6.16 min m/z=241; TLC: Hex/EtOAC [10:1] Rf=0.34, major spot, >95%,light impurity at origin.

[0181] (b) Preparation of 3,3-bis(4-fluorophenyl)propionitrile

[0182] A solution of 9.53 g, 39.5 mmol of aklene-nitrile dissolved inEtOH (80 mL) was hydrogenated at 60 psig H₂ over 10% Pd(OH)₂/C (20% Pd,Fluka, 1.90 g). After shaking for 8 h, the catalyst was removed byfiltration through fritted glass. The solvent in the filtrate wasevaporated under vacuum and the crude product was isolated as an oil.This material was chromatographed (50 mm×30 cm, elution withhexane/ethyl acetate [10:1] to [8:1]). Fractions containing product werecombined and evaporated to provide 9.66 g, 100% of product as a yellowoil. GC/EIMS, Rt=7.18 min, m/z=243; TLC.

[0183] (c) Preparation of 3,3-bis(4-fluorophenyl)propanamide

[0184] The nitrile (9.66 g, 39.8 mmol) was dissolved into conc. H₂SO₄(12 mL). The reaction solution was then stirred for 15 min at roomtemperature followed by 15 min at 50° C. Water (200 mL) was added to thecooled reaction mixture followed by ethyl acetate (100 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (100 mL).The combined organic layers were washed with H₂O (2×50 mL), sat. aq.NaHCO₃ (50 mL), dried (anhydr. Na₂SO₄), and evaporated under vacuum toprovide crude product. This material was chromatographed (50×300 mm,elution with ethyl acetate/hexane [1:3]). Fractions containing productwere combined and evaporated to provide 2.34 g, 22.5% of product as awhite solid. GC/MS, Rt=7.93 min m/z=261; TLC: Hex/EtOAc [1:1], Rf=0.20,single spot UV/Vis; ¹H-NMR 2.87 (d, J=8 Hz, 2H), 4.55 (t, J=8 Hz, 1H),5.38 (bs, 1H), 5.63 (bs, 1H), 6.94-7.00 (m, 4H), 7.15-7.19 (m, 4H).

[0185] Synthesis of N-isopropyl 3,3-bis(3-fluorophenyl)propanamide(Compound 4)

[0186] To a −78° C. solution of the acid chloride (5 g, 17.8 mmol [15.5mmol actual]) in CH₂Cl₂ (50 mL) was added in a stream isopropylamine(4.6 mL, 3.16 g, 53.5 mmol, 3 equivt). The dry-ice bath was removed andthe reaction mixture was then stirred for 4 h at room temperature. Themixture was then poured into diethyl ether (100 mL) and the organiclayer was washed with 1 M HCl (4×50 mL), 1 M NaOH (3×50 mL), and H₂O(3×50 mL). The organic layer was then filtered (paper), dried (anhydr.Na₂SO₄), filtered again, and the solvent was removed under vacuum toprovide 3.17 g, 71% of product as a cream-colored powder. TLC analysis:Hex/EtOAc [3:1], showed one major spot. This material was recrystallizedfrom abs. EtOH/H₂O [1:1] (60 mL) plus abs. H₂O (10 mL, to cloudpoint) toprovide 3.06 g, 68% yield of product as a chalky, white powder. TLC:Hex/EtOAc [1:1], Rf=0.53; GC/EIMS, Rt=7.55 min, m/z 303.

[0187] Synthesis ofN-[(3-hydroxy-2-methyl)-2-propyl]-3,3-bis(3-fluorophenyl)propanamide(Compound 6)

[0188] To a −78° C. solution of the acid chloride (5 g, 17.8 mmol [15.5mmol actual]) in CH₂Cl₂ (50 mL) was added in a stream ethanolamine (5.1mL, 4.77 g, 53.5 mmol, 3 equivt). The dry-ice bath was removed and thereaction mixture was then stirred at room temperature. The mixture wasthen poured into ethyl acetate (100 mL) and the organic layer was washedwith 1 M HCl/sat. with NaCl (2×50 mL), 1 M NaOH/sat. with NaCl (2×50mL), and sat. aq. NaCl (2×50 mL). The organic layer was then filtered(paper), dried (anhydr. Na₂SO₄), filtered again, and the solvent wasremoved under vacuum to provide ˜4 g of product as an off-white powder.TLC analysis: Hex/EtOAc [3:1], showed one major spot. This material wasrecrystallized from abs. EtOH/H₂O [1:1] (50 mL) plus abs. H₂O (40 mL, tocloudpoint) to provide 2.70 g, 47.6% yield of product as a white powder.TLC: Hex/EtOAc [1:1], Rf=0.27; GC/EIMS Rt=6.80 min, m/z=315 (dehydrationproduct), GC/EIMS, inconclusive mixture; ¹H-NMR analysis indicatedproduct present and of high purity.

[0189] Synthesis of N-methyl-2,2-bis(4-fluorophenyl)acetamide (Compound14)

[0190] (a) Preparation of 2,2-bis(4-fluorophenyl)acetic Acid

[0191] To 4,4′-difluorobenzhydrol (10.0 g, 45.4 mmol, 1 equiv) in H₂SO₄(37 M; 200 mL, 7.4 mol, 160 equiv) in an ice bath was added formic acid(20 mL, 24 g, 0.53 mol, 12 equiv) with no stirring. After a few seconds,carbon monoxide evolution was observed. The reaction was allowed tostand without stirring for 3.5 h. The reaction mixture was carefullypoured into H₂O (1000 ML) (highly exothermic). The aqueous mixture wasextracted with EtOAc (1×250 mL) The organic layer was dried (anh.Na₂SO₄) and rotary evaporated (75° C.) to yield 11.7 g of an orange oil.This oil was dissolved in Et₂O (100 mL) and extracted with 2 M NaOH(1×50 mL). The aqueous layer was then acidified with 12 M HCl (8 mL) andextracted with EtOAc (1×50 mL). The organic layer was dried (anh.Na₂SO₄), rotary evaporated (75° C.), and put under high vacuum for 16 h.This provided 6.15 g (54.6%) of product as a yellow, crystalline solid.

[0192] (b) Preparation of 2,2-bis(4-fluorophenyl)acetyl Chloride

[0193] The carboxylic acid (6.15 g, 24.8 mmol, 1 equiv) in thionylchloride (12 mL, 20 g, 160 mmol, 6.6 equiv) was refluxed under N₂ for 2h. The reaction solution was then rotary evaporated (95° C.). Thisprovided 6.45 g (97.6%) of product as an orange-brown oil.

[0194] (c) Preparation of N-methyl-2,2-bis(4-fluorophenyl)acetamide

[0195] Methylamine (40% in H₂O; 1.5 mL, 1.4 g, 0.54 g amine, 17 mmol,3.1 equiv) was diluted with H₂O (30 mL). The acid chloride (1.50 g, 5.62mmol, 1 equiv) in EtOAc (30 mL) was added to the vigorously stirringaqueous solution over a period of 3 min. The biphasic reaction mixturewas stirred vigorously for 15 min. The organic layer was separated andwashed with 1 M HCl/satd. aq. NaCl (3×10 mL), 1 M NaOH/satd. aq. NaCl(2×10 mL), and satd. aq. NaCl (2×10 mL). The organic layer was thendried (anh. Na₂SO₄), rotary evaporated (75° C.), and put under highvacuum for 17 h. This provided 1.19 g (81.0%) of product as anoff-white, finely crystalline solid. This solid was dissolved in EtOAc(25 mL) and filtered through a 0.45 -μm filter disc. Hexanes (25 mL)were added to the filtrate. The crystallizing solution was allowed tostand for 15 min. The resulting crystals were filtered, washed withhexanes (2×25 mL), and dried under high vacuum for 22 h. This provided547 mg (37.2%) of product as a white, finely crystalline solid.

[0196] These and other examples and compounds of the present inventioncan be readily prepared by skilled artisans using similar, analogous,and/or homologous synthetic methods known to those in the art.

[0197] Other embodiments are within the following claims.

1. A compound having the formula

wherein: Y is independently selected from the group consisting of —H,—F, and —Cl; X is either —NR¹R² or —OR¹; R¹ is selected from the groupconsisting,of —H, alkyl, and hydroxyalkyl; R² is selected from the groupconsisting of —H, methyl, and ethyl; and n is either 0, 1, 2, 3, or 4,except for 3,3-bis(3-fluorophenyl)propanamide,N-methyl-3,3-bis(3-fluorophenyl) propanamide,N-ethyl-3,3-bis(3-fluorophenyl)propanamide,N,N-dimethyl-3,3-bis(3-fluorophenyl)propanamide, andN,N-diethyl-3,3-bis(3-fluorophenyl)propanamide.
 2. A compound having theformula

wherein: each F is independently in either the meta- or para-position;R¹ is selected from the group consisting of —H, alkyl, and hydroxyalkyl;R² is selected from the group consisting of —H, methyl, and ethyl; and nis 0, 1, 2, 3, or 4, except for 3,3-bis(3-fluorophenyl)propanamide,N-methyl-3,3-bis(3-fluorophenyl)propanamide,N-ethyl-3,3-bis(3-fluorophenyl)propanamide,N,N-dimethyl-3,3-bis(3-fluorophenyl)propanamide, andN,N-diethyl-3,3-bis(3-fluorophenyl)propanamide.
 3. The compound of claim1, wherein R¹ is selected from the group consisting of —H, methyl,ethyl, isopropyl, isobutyl, tert-butyl, hydroxyisopropyl, andhydroxyethyl, and R² is —H.
 4. A compound having the formula

wherein: n is 0, 1, or 2; both F are either in the meta- orpara-position; R¹ is selected-from the group consisting of —H, alkyl,and hydroxyalkyl; and R²is selected from the group consisting of —H,methyl, and ethyl, except for 3,3-bis(3-fluorophenyl)propanamide,N-methyl-3,3-bis(3-fluorophenyl)propanamide,N-ethyl-3,3-bis(3-fluorophenyl)propanamide,N,N-dimethyl-3,3-bis(3-fluorophenyl)propanamide, andN,N-diethyl-3,3-bis(3-fluorophenyl)propanamide.
 5. The compound of claim1, wherein said compound is selected from the group consisting ofcompound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and18.
 6. The compound of claim 1, wherein said compound is selected fromthe group consisting of Compound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14,and
 15. 7. The compound of claim 1, wherein said compound is Compound 1.8. A method for treating a patient having a neurological disease ordisorder comprising administering a compound having the formula

wherein: Y is independently selected from the group consisting of —H,—F, and —Cl; X is either —NR¹R² or —OR¹; R¹ is selected from the groupconsisting of —H, alkyl, and hydroxyalkyl; R² is selected from the groupconsisting of —H, methyl, and ethyl; and n is either 0, 1, 2, 3, or 4 9.The method of claim 8, wherein R¹ is selected from the group consistingof —H, methyl, ethyl, isopropyl, isobutyl, hydroxyisopropyl, andhydroxyethyl, and R² is —H.
 10. The method of claim 8, wherein saidcompound is selected from the group consisting of compounds 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and
 18. 11. The method ofclaim 8, wherein said compound is selected from the group consisting ofCompound 1, 2, 3, 7, 8, 9, 10, 11, 12, 13, 14, and
 15. 12. The method ofclaim 8 wherein said compound is compound
 1. 13. A method for treating apatient having a neurological disease or disorder comprisingadministering a compound having the formula

wherein: each F is independently in either the meta- or para-position;R¹ is selected from the group consisting of —H, alkyl, and hydroxyalkyl;R² is selected from the group consisting of —H, methyl, and ethyl; and nis 0, 1, 2, 3, or
 4. 14. A method for treating a patient having aneurological disease or disorder comprising administering a compoundhaving the formula

wherein: n is 0, 1, or 2; both F are either in the meta- orpara-position; R¹ is selected from the group consisting of —H, alkyl,and hydroxyalkyl; and R² is selected from the group consisting of —H,methyl, and ethyl.
 15. The method of claim 8, wherein said neurologicaldisease or disorder is selected from the group consisting of epilepsy,convulsions, and seizure disorders.
 16. The method of claim 8, whereinsaid treating of said patient alleviates or prevents convulsions in saidpatient.
 17. The method of claim 8, wherein said neurological disease ordisorder is associated with spasticity.
 18. The method of claim 15,wherein said neurological disease or disorder is a neurodegenerativedisease or disorder.
 19. The method of claim 8, wherein saidneurological disease or disorder is selected from the group consistingof spasticity, skeletal muscle spasms, restless leg syndrome, anxiety,stress, multiple sclerosis, stroke, head trauma, spinal cord injury,Parkinson's disease, Huntington's disease, Alzheimers disease,amyotrophic lateral sclerosis, migraine headaches, and bipolar disorder.20. A method of alleviating or preventing a symptom of spasticity, orone or more side effects of spasticity, in a patient comprisingadministering a compound of any of claims 1-4, or
 7. 21. Apharmaceutical composition, comprising a compound of claim 1, and apharmaceutically acceptable carrier.
 22. A pharmaceutical composition,comprising a compound of claim 2, and a pharmaceutically acceptablecarrier.
 23. A pharmaceutical composition, comprising a compound ofclaim 3, and a pharmaceutically acceptable carrier.
 24. A pharmaceuticalcomposition, comprising a compound of claim 4, and a pharmaceuticallyacceptable carrier.
 25. A pharmaceutical composition, comprising acompound of claim 5, and a pharmaceutically acceptable carrier.
 26. Apharmaceutical composition, comprising a compound of claim 7, and apharmaceutically acceptable carrier.
 27. A method for making atherapeutic agent comprising the steps of screening for said agent bydetermining whether said agent alleviates a symptom of spasticity, andsynthesizing said therapeutic agent in an amount sufficient to providesaid agent in a therapeutically effective amount to a patient.
 28. Themethod of claim 18, wherein said therapeutic agent comprises a compoundof claim
 1. 29. A method for modulating CNS activity comprisingadministering to a patient a compound of claim
 1. 30. The method ofclaim 29, wherein said modulation of CNS activity alleviates a symptomassociated with convulsions, spasticity, an affective mood disorder, aneuropathic pain syndrome, a headache, a restlessness syndrome, or amovement disorder.